Genetic regulation of racial differences in platelet reactivity

血小板反应性种族差异的基因调控

• 批准号: 9501315
• 负责人: PAUL F. BRAY
• 金额: $ 37.88万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-09 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9501315
• 关键词: 12-HETE; 14q32; Accounting; Address; Adverse effects; Arterial Fatty Streak; Automobile Driving; Biochemical; Biochemistry; Bioinformatics; Biological; Black race; Blood Platelets; Candidate Disease Gene; Cells; Cellular biology; Chromosomes; Clinical; Coronary artery; Coronary heart disease; CpG Islands; Critical Pathways; Data; Economics; Event; F2R gene; Fatty Acids; Gene Expression; Genes; Genetic; Genome; Genomics; Goals; Human; Incidence; Kinetics; Lipids; Mediating; Megakaryocytes; Messenger RNA; MicroRNAs; Molecular; Molecular Genetics; Morbidity - disease rate; Movement; Myocardial Infarction; PAWR gene; Phospholipase A2; Physiological; Physiology; Platelet Activation; Platelet aggregation; Population; Process; Production; Protein Family; Proteins; Race; Recruitment Activity; Regulation; Research Design; Role; Rupture; Signal Pathway; Signal Transduction; Signaling Protein; Site; Stroke; System; Thrombin Receptor; Thrombosis; Thromboxanes; Thrombus; Time; Transcript; Variant; bisulfite; cohort; differential expression; experimental study; high risk; imprint; mortality; novel; overexpression; personalized management; phosphatidylcholine transfer protein; protein complex; protein function; public health relevance; pyrosequencing; racial difference; racial disparity; ras-GRF2; receptor; release of sequestered calcium ion into cytoplasm; socioeconomics

DESCRIPTION (provided by applicant): Coronary heart disease (CHD) is the most common killer in both whites and blacks. However, blacks have a 2- fold increase in the incidence of CHD as well as a lower long-term survival compared to whites. These differences cannot be fully explained by demographic, clinical, or economic confounders between these groups. As myocardial infarction and stroke typically result from an occlusive platelet thrombus formed at the site of a ruptured atherosclerotic plaque, understanding differences in the mechanisms by which platelets are activated in blacks and whites is expected to aid in our ability to optimally treat these populations following myocardial infarction (MI) and stroke. Our preliminary data demonstrates, for the first time, 1) racial differences in PAR4-mediated platelet aggregation, and 2) platelet mRNAs and microRNAs that are differentially expressed (DE) between blacks and whites and regulate PRA4 activation. The goals of this application are to characterize 1) the critical pathways and proteins responsible for these racial differences in platelet function, and 2 the molecular genetic basis for differences in gene expression. These goals will be addressed with physiology, biochemistry, genomic and cell biology approaches in human platelets and megakaryocytes. Aim 1 will dissect racial differences in platelet function using physiological and biochemical endpoints to assess PAR4 activation kinetics and absolute level of activity. By integrating the information attained in Aim 1, Aim 2 will evaluate novel candidate platelet genes DE expressed between blacks and whites. These genes will be characterized for their potential role in regulating the racial difference in PAR4-mediated reactivity of platelets. In particular, w find phosphatidylcholine transfer protein (PC-TP), is significantly higher in platelets from blacks compared to platelets from whites. PC-TP regulates lipid movement in the cell, a critical process in platelet activation. Several other strong candidate platelet genes - also DE by race - will also be characterized. Aim 3 will focus on novel mechanisms of gene expression that account for racial differences in platelet aggregation. We have identified the first example of miRNAs that are DE by race and by PAR4-mediated platelet aggregation. We will genetically manipulate candidate miRNAs in cultured human megakaryocytes to assess their effects on regulating PAR4-mediated platelet/megakaryocyte reactivity. We will also assess the molecular basis for the differential expression of miRNAs. This study will be the first to characterize racial differences in platelet activation at the signaling, protein and genetic levels. Understanding the racial difference in platelet activity will fill a significant gap in our understanding of why blacs suffer a higher morbidity and mortality than whites following MI and stroke.

描述（由申请人提供）：冠心病（CHD）是白人和黑人最常见的杀手。然而，与白人相比，黑人的发生率增加了2倍，而长期存活率较低。这些群体之间的人口，临床或经济混杂因素无法完全解释这些差异。由于心肌梗死和中风通常是由于在破裂的动脉粥样硬化斑块上形成的闭塞血小板血栓引起的，因此了解在黑人和白人中激活血小板的机制的差异，预计有助于我们能够在我们的能力上进行最佳治疗这些群体，以便我们在心肌治疗这些群体后有助于最佳地治疗这些群体。梗塞（MI）和中风。我们的初步数据首次证明了1）PAR4介导的血小板聚集的种族差异，以及2）黑人和白人之间差异表达（DE）的血小板mRNA和microRNA，并调节PRA4激活。该应用的目标是表征1）造成血小板功能这些种族差异的关键途径和蛋白质，以及基因表达差异的分子遗传基础。这些目标将通过人血小板和巨核细胞的生理学，生物化学，基因组和细胞生物学方法来解决。 AIM 1将使用生理和生化终点来剖析血小板功能的种族差异，以评估PAR4激活动力学和绝对活动水平。通过整合在AIM 1中获得的信息，AIM 2将评估黑人和白人之间表达的新型候选血小板基因。这些基因在调节PAR4介导的血小板反应性中的种族差异中的潜在作用将被特征。特别是，在黑人的血小板中，发现磷脂酰胆碱转移蛋白（PC-TP）明显更高 与白人的血小板相比。 PC-TP调节细胞中的脂质运动，这是血小板激活的关键过程。其他几个强大的候选血小板基因（也是种族）也将 被描述。 AIM 3将重点关注基因表达的新机制，这些机制解释了血小板聚集的种族差异。我们已经确定了由种族和PAR4介导的血小板聚集的miRNA的第一个例子。我们将在培养的人类巨核细胞中遗传操纵候选miRNA，以评估其对调节PAR4介导的血小板/巨核细胞反应性的影响。我们还将评估miRNA差异表达的分子基础。这项研究将是第一个在信号，蛋白质和遗传水平下血小板激活中种族差异的表征。了解血小板活动的种族差异将填补我们对为什么BLAC的发病率和死亡率比MI和中风后的白人更高的理解。